Risk factors of recurrence after robot-assisted laparoscopic partial nephrectomy for solitary localized renal cell carcinoma

To evaluate the recurrence rate and risk factors of recurrence after robot-assisted laparoscopic partial nephrectomy for solitary renal cell carcinoma (RCC). A total of 1265 cases of initial solitary localized RCC were analyzed. The baseline characteristics, complexity (REANL nephrometry score), intra- and peri-operative outcomes, and recurrence were evaluated. Logistic regression was performed to evaluate the factors affecting recurrence after RAPN for solitary localized RCC. Recurrence after robot-assisted partial nephrectomy (RAPN) occurred in 29 patients (2.29%). The median follow-up was 36.0 months. The N domain (nearness to collecting system/sinus) (odd ratio (OR) 3.517, 95% confidence interval (CI) 1.557–7.945, p = 0.002), operation time (OR 1.005, 95% CI 1.001–1.010, p = 0.013), and perioperative transfusion (OR 5.450, 95% CI 1.197–24.816, p = 0.028) affected recurrence. Distant metastasis among patients with recurrence was significantly associated with nearness to the collecting system/sinus (OR 2.982, 95% CI 1.162–7.656, p = 0.023) and distance between the mass and collecting system/sinus (OR 0.758, 95% CI 0.594–0.967, p = 0.026). Nearness to the collecting system/sinus, operation time, and perioperative transfusion affect recurrence after RAPN for solitary localized RCC. Moreover, the proximity to the collecting system/sinus and distance between the mass and collecting system/sinus were significantly related to distant metastasis after RAPN.


Discussion
Nearness to the collecting system/sinus, operation time, and perioperative transfusion affect recurrence after RAPN.In particular, proximity to the collecting system/sinus and the distance between the mass and collecting system/sinus are significantly related to distant metastasis.
As a treatment for clinically localized small renal masses, PN showed similar surgery-related mortality, cancer-specific survival, and time-to-recurrence with superiority in decreased time-to-death from any cause compared to radical nephrectomy 12 .Moreover, compared to radical nephrectomy, PN as a treatment for large renal masses (T1b or T2) also has equivalent cancer control and better preservation of renal function with the potential for better long-term survival 13 .However, there are few studies on the risk factors for recurrence after PN for RCC.Recently, through a systematic review, Henderickx et al. reported that a PSM was a risk factor for local recurrence; the percentage of cases with a PSM ranged from 0 to 34.4% and local recurrence varied from 0 to 9.1% 11 .In the present study, PSM was defined as the presence of malignant cells at the surgical margin in the pathologic report, and only six RAPN patients (0.41%) were evaluated as having a PSM..However, in RAPN, the surgeon factor cannot be avoided in PSM.Although the association between recurrence and PSM could not be clearly confirmed due to the very low incidence of PSMs in this study, reducing PSMs is needed for better oncological outcomes.Tumor incision is a known risk factor for tumor recurrence and metastasis 15 .However, in our results, there was no significant relationship between capsular incision and tumor recurrence.Moreover, a retrospective study by Ito et al. reported that capsular incision during PN was not associated with poor oncological outcomes 16 .However, in both results, the number of capsular incisions was too small to draw definitive conclusions.Yoshino et al. reported that RCC cells remained on the surface of the scissors after capsular incision, and elimination of the tumor cell using monopolar electrical treatment is needed 17 .In addition, Li et al. suggested that capsular incision would affect tumor recurrence and recommended that scissors be treated with povidone-iodine after capsular incision 18 .Although there is no definite conclusion regarding the effect of capsular incision on recurrence, if capsular incision occurs, it is necessary to secure a safe surgical margin through additional resection and treatment of the scissor surface.In this study, the incidence of capsular incision and PSM was low, and appropriate evaluations could not be assessed.However, avoiding obvious risk factors such as tumor violation or margin status could improve oncological outcomes.
In our results, the N domain (nearness to collecting system/sinus) in the RENAL nephrometry score was significantly related to recurrence.Maxwell et al. also reported that the N domain had a significant effect on recurrence after thermal ablation (hazard ratio 3.15, 95% confidence intervals 1.31-7.62,p < 0.0001) 19 .Unlike the present study, they reported that the R domain (the diameter of the mass) was associated with recurrence.This may be due to the difference in the treatment characteristics of ablation and surgical resection.Additionally, propensity score matching was performed for familial history, hypertension, and clinical T stage to further assess the risk of N domain recurrence.After matching, there was no statistical difference in the baseline characteristics (Supplementary 1), and through logistic regression, the N domain was the only factor that significantly affected recurrence (Supplementary 2).
In the present study, operation time also affected recurrence.This may be due to the longer tumor manipulation time than the surgical time itself.Wan et al. reported that high plasma cell-free DNA levels were associated with a significantly higher recurrence rate in clear cell RCC 20 .Although it has not been reported that tumor manipulation increases circulating tumor cells during PN, it is known that surgical management www.nature.com/scientificreports/causes dissemination of circulating tumor cells 21 .Even in the case of RCC, if the tumor manipulation time is prolonged, the level of circulating tumor cells may increase, which could affect recurrence.Moreover, nearness to the collecting system/sinus and the distance between the mass and collecting system/sinus were associated with distant metastasis in our results.It is possible that the level of circulating tumor cells during surgery might increase more when the sinus and tumor are closer.Further evaluation using a prospective study is required.Abu-Ghanem et al. reported that perioperative blood transfusion was associated with reduced recurrence-free, cancer-specific, and overall survival in patients undergoing nephrectomy for RCC 22 .Our results also showed that perioperative blood transfusion was associated with tumor recurrence after RAPN.The mechanism of the adverse oncological effects in transfusion may be related to the suppressive effects on the immune system 23,24 .Moreover, transient immune impairment, which comes from transfusion, may enhance a condition favorable to cancer cells 25 .However, there is still controversy regarding transfusion and oncological outcomes in RCC.
This was a retrospective study, and its limitation was the relatively short follow-up period.Moreover, whether the recurrence in ipsilateral RCC was an incidental lesion or a metastatic lesion was not clearly determined.However, a pathological review was performed in all 10 cases, and the histology was confirmed to be the same as that of previous RCC on biopsy.The bias may have been reduced with the data of a single expert surgeon, which can reduce the surgeon factor.In addition, this study is significant in that it is the first large-scale study to evaluate risk factors for recurrence after RAPN as a treatment for solitary RCC.

Patients
A total of 1465 patients who underwent RAPN between 2008 and 2022 were retrospectively analyzed.RAPN was performed by a single expert surgeon.RAPN was performed when it was determined that nephron-sparing surgery was possible for a localized renal mass of T1 or T2 stage.We excluded patients with multiple renal masses, non-RCC, lymph node invasion, and recurrent masses from this study.
Among these patients, 1265 cases of initial solitary localized RCC were selected based on pathological reports (Fig. 1).To evaluate the recurrence risk factors after RAPN as a treatment for solitary RCC, the recurrence and no recurrence groups were compared.www.nature.com/scientificreports/

Clinicopathologic assessment
The baseline characteristics of the patients, including age at RAPN, underlying disease, familial history, routine laboratory test, and diethylenetriamine pentaacetic acid renal scan were evaluated.Abdominal computed tomography (CT) with/without magnetic resonance imaging (MRI) was performed on the patient, and complexity was evaluated using the RENAL nephrometry score 26 .Estimated blood loss, warm ischemic time, capsular incision, and intraoperative complications, including transfusion, were evaluated.In addition, the length of hospital stay and perioperative complications were evaluated.The histopathology was evaluated by experienced uropathologists.

Follow up
After RAPN, the patients were generally followed up every 3-6 months in the first year.Thereafter, follow-up was performed at intervals of 6-12 months.Patients underwent abdominal CT or MRI, chest radiography, and routine laboratory tests at each visit.Recurrence-free survival was defined as the interval between the date of surgery and the time of the first tumor recurrence.The cause of death was determined by the physicians responsible and death certificates.www.nature.com/scientificreports/

Surgical approach
The operation was performed using a four-arm da Vinci Robotic System (Intuitive Surgical, Seoul, Korea), using five ports.Based on the location of the renal mass, a retroperitoneal or transperitoneal approach was performed according to the surgeon's decision.The operation was performed through main artery clamping without selective ischemia, and PN was performed under warm ischemia in all patients.In most cases, tumor excision uses a

Table 2 .
Surgical and oncological outcomes.Student's t test, Chi-square test.

Table 3 .
Logistic regression analysis for tumor recurrence after robot assisted laparoscopic partial nephrectomy for solitary renal cell carcinoma.ASA American Society of Anesthesiologists, CI confidence interval, GFR Glomerular filtration rate, OR odds ratio.

Table 4 .
Logistic regression analysis for distant metastasis in tumor recurrence after robot assisted laparoscopic partial nephrectomy for solitary renal cell carcinoma (n = 29).OR odds ratio, CI confidence interval.